HIV strains used in this project included a laboratory strain (HIV- 1IIIB), monocytotropic strain (HIV-1Ba-L), and primary HIV strains isolated from AIDS patients in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PHA- PBM). Target cells used included CD4+ ATH8 cells, purified monocytes/macrophages (M/M), and PHA/PBM. Endpoints used included the inhibition of the cytopathic effect (CPE) of HIV-1 and p24 Gag protein production by target cells, following HIV exposure. Analysis of drug interactions was performed using the COMBO program. We found that all protease inhibitors tested exhibited a significant inhibition of the CPE against ATH8 cells with a range of 50% inhibitory concentrations (IC50) being 0.06 - 1.8 um. In addition, they completely inhibited the replication of HIV-1Ba-L in M/M at 0.75 - 2 uM throughout 26 days of culture. A potent inhibitory activity against primary HIV isolates was also observed with IC50 ranging from 0.09 to 0.22 uM for all three compounds when PHA/PBM were employed as target cells. Cellular toxicity was neglible at the highest concentrations used (up to 10 Um). When the protease inhibitors and dideoxynucleosides were used in combination against primary HIV isolates, their antiviral activities appeared additive in some cases and synergistic in others. We conclude that C2 symmetric HIV protease inhibitors tested in this study had a potent antiviral activity against a wide range of HIV isolates including monocytotropic strains and primary HIV isolates, and they represent promising experimental antiviral agents for the therapy of HIV infection.